NGF Signaling in Sensory Neurons

Abstract

Target-derived NGF promotes the phenotypic maintenance of mature dorsal root ganglion (DRG) nociceptive neurons. Here, we provide in vivo and in vitro evidence for the presence within DRG neurons of endosomes containing NGF, activated TrkA, and signaling proteins of the Rap1/Erk1/2, p38MAPK, and PI3K/Akt pathways. Signaling endosomes were shown to be retrogradely transported in the isolated sciatic nerve in vitro. NGF injection in the peripheral target of DRG neurons increased the retrograde transport of p-Erk1/2, p-p38, and pAkt in these membranes. Conversely, NGF antibody injections decreased the retrograde transport of p-Erk1/2 and p-p38. Our results are evidence that signaling endosomes, with the characteristics of early endosomes, convey NGF signals from the target of nociceptive neurons to their cell bodies.

Interaction of the Wiskott–Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells

“…A connection of CD28 endocytosis with its cosignaling function is implied by data showing that the HIV accessory protein, Nef, enhances induction of both CD28 endocytosis and T cell activation (54,55). Similarly, linkages of endocytic pathway components with cell signaling/activation are suggested by the capacities of intersectins, dynamin, and other endocytic effectors to interact with signaling effectors like Src and Sos to promote MAP kinase pathway activation (51,56,57) and data showing that signaling protein-containing endosomes, for example, in sensory neurons, contribute to transduction of growth factor-activating signals (58). These data suggest that endosomes can serve as signaling platforms enabling the intersection of endocytic, actin regulatory, and signaling proteins.…”

One at a time, live tracking of NGF axonal transport using quantum dots

“…To show that QD-NGF containing endosomes carry the NGF signal, we examined the distribution of these endosomes with respect to that of signaling proteins that were shown to mediate NGF signaling and associate with retrogradely transported endosomes under physiological conditions (11,38). For this study, we adopted a modified version of microfluidic nerve cell chamber (39), which enhances the ability to image and track QD signals (Fig.…”

“…After 2 h of incubation, cells were extensively rinsed, fixed and stained with antibodies to Trk, pErk1/2 (i.e., activated Erk1/2) by using established protocols (11). Rab5, a marker of early endosomes, was also examined.…”

“…The elucidation of the mechanism(s) used to transmit NGF signal from the terminals of axons to cell bodies of neurons is yet to be fully defined. In that retrograde NGF signaling is critical for the survival and maintenance of neurons of both the peripheral and central nervous systems, and the underlying mechanisms are likely to be shared by related neurotrophic factors, the issue remains one of the most significant and intriguing questions in neurobiology (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…Moreover, few studies have examined NGF-containing endosomes during axonal transit. Some have suggested that NGF is transported principally within early endosomes (4,5,(7)(8)(9)(10)(11)(12)(13)(14) whereas others suggest that NGF is transported in organelles with complex membrane structures such as multivesicular bodies (MVBs) (8,20) and in macropinosomes (23).…”